Alignment of stroma fibers, microvessel density and immune cell populations determine overall survival in pancreatic cancer—An analysis of stromal morphology

Bolm, Louisa; Zghurskyi, Petro; Lapshyn, Hryhoriy; Petrova, Ekaterina; Земсков, Сергій; Vashist, Yogesh K.; Deichmann, Steffen; Honselmann, Kim C.; Bronsert, Peter; Keck, Tobias; Wellner, Ulrich F.

doi:10.1371/journal.pone.0234568

Cited by 14 publications

(10 citation statements)

References 39 publications

(57 reference statements)

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“…Therefore, PRO-C6 may be a measure of collagen alignment (anisotropy). Clinically, collagen fiber alignment is a negative prognostic factor in PDAC [12,77]. This might be due to the fact that fiber alignment promotes migration, by being highways for cancer cells to travel on, and furthermore, highly aligned fibers result in stiff tissue, which increases interstitial fluid pressure, resulting in reduced drug uptake and thereby treatment resistantcy [78][79][80].…”

Section: Discussionmentioning

confidence: 99%

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

Nissen

Johansen

Chen

et al. 2022

Cancers

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The use of novel tools to understand tumour-fibrosis in pancreatic ductal adenocarcinoma (PDAC) and novel anti-fibrotic treatments are highly needed. We established a pseudo-3D in vitro model including humane pancreatic fibroblasts (PFs) and pancreatic cancer-associated fibroblasts (CAFs) in combination with clinical collagen biomarkers, as a translational anti-fibrotic drug screening tool. Furthermore, we investigated the prognostic potential of serum collagen biomarkers in 810 patients with PDAC. PFs and CAFs were cultured in Ficoll-media. Cells were treated w/wo TGF-ß1 and the anti-fibrotic compound ALK5i. Biomarkers measuring the formation of type III (PRO-C3) and VI (PRO-C6) collagens were measured by ELISA in supernatant at days 3, 6, 9, and 12. PRO-C3 and PRO-C6, and their association with overall survival (OS), were evaluated in serum with PDAC (n = 810). PRO-C3 and PRO-C6 were upregulated in CAFs compared to PFs (p < 0.0001.). TGF-ß1 increased PRO-C3 in both PFs and CAFs (p < 0.0001). The anti-fibrotic compound ALK5i inhibited both PRO-C3 and PRO-C6 (p < 0.0001). High serum levels of PRO-C3 and PRO-C6 in patients with PDAC were associated with short OS (PRO-C3:HR= 1.48, 95%CI:1.29–1.71, p < 0.0001 and PRO-C6:HR = 1.31, 95%CI:1.14–1.50, p = 0.0002). PRO-C3 and PRO-C6 have the potential to be used both pre-clinically and clinically as a measure of tumor fibrosis and CAF activity.

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Section: Discussionmentioning

confidence: 99%

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

Nissen

Johansen

Chen

et al. 2022

Cancers

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“…This finding is consistent with the literature, which shows that high collagen fiber alignment specifically, rather than high collagen density, is a negative prognostic indicator in PDAC patients. [25,55] Here, remediation of desmoplasia by TPMIL + 690 nm (12.5 PDT dose product) is partially attributed to dose-dependent photochemical degradation of collagen. [18] At low PDT doses (<25 J cm −2 ), the stiffness of collagen hydrogels increases, likely due to collagen crosslinking.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Remediating Desmoplasia with EGFR‐Targeted Photoactivable Multi‐Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer

et al. 2022

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Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5‐year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi‐inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti‐EGFR mAb) contain lipidated benzoporphyrin derivative (BPD‐PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient‐derived cancer‐associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal‐IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne‐photodynamic therapy (PDT) and nal‐IRI, and also doubles survival and extends progression‐free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103‐fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single‐construct phototoxic, chemotherapeutic, and desmoplasia‐remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.

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“…Numerous studies have shown that PaC is a hypovascular and hypoxic solid tumor, and PaC tissue frequently exhibits aberrant proliferation of human vascular endothelial cells (HUVECs) [50,51]. Moreover, it is reported that the microvessel density (MVD) in tumor tissue is positively correlated with the progression of PaC [52][53][54][55].…”

Section: Lncrna-uca1 Promotes the Tumor Angiogenesis In Pacmentioning

confidence: 99%

The Functional Role of LncRNA UCA1 in Pancreatic Cancer: a mini-review

Sun¹,

Li²,

jiang³

et al. 2023

J. Cancer

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Pancreatic cancer (PaC) is a common malignant tumor of the digestive tract, with a 5-year survival rate of less than 5% and high mortality rate in the world. LncRNAs have been showed to possess multiple biological functions in growth, differentiation, and proliferation, which play an important role in different biological processes and diseases, especially in the development of tumors. LncRNA UCA1, which is firstly identified in human bladder cancer, has been showed to be a tumor promoter in pancreatic cancer. Recent researches have showed that UCA1 might promote pancreatic carcinogenesis and progression, and correlate with drug resistance. In this review, we address the biological function and regulatory mechanism of UCA1 in pancreatic cancer, which might give a new approach for clinical diagnosis and treatment.

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Alignment of stroma fibers, microvessel density and immune cell populations determine overall survival in pancreatic cancer—An analysis of stromal morphology

Cited by 14 publications

References 39 publications

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

Remediating Desmoplasia with EGFR‐Targeted Photoactivable Multi‐Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer

The Functional Role of LncRNA UCA1 in Pancreatic Cancer: a mini-review

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